Bone morphogenetic proteins (BMPs) are multifunctional growth factors that are members of the transforming growth factor β (TGFβ) superfamily. BMP signaling plays a role in heart, neural, and cartilage development as well as in postnatal bone formation. BMPs induce a cascade of endochondral bone formation and play a decisive role in skeletal and joint morphogenesis (Urist, Science, 150:893-899 (1965), Olsen et al., Annu. Rev. Cell Dev. Biol. 16:191-220 (2000), Kronenberg, Nature 423:332-336 (2003), Thomas et al., Nat. Genet. 12:315-317 (1996), Thomas et al., Nat. Genet. 17:58-64 (1997), Polinkowsky et al., Nat. Genet. 17:18-19 (1997), Storm et al., Nature, 368:639-643 (1994)).
BMPs signal through serine/threonine kinase receptors including both types 1 and 2. Three type 1 receptors [type 1a and 1b BMP receptors and type 1 activin receptor (ActRI)] bind to BMP ligands (Koenig et al., Mol. Cell. Biol. 14:5961-5974 (1994), Ten Dijke et al., J. Biol Chem. 269:16985-16988 (1994), Macias-Silva et al., J. Biol. Chem. 273:25628-25636 (1998)).
BMPs are synthesized as large dimeric precursor-proteins in the cytoplasm, and cleaved by proteases during secretion. Each monomer contains about 300 amino acids as the precursor proteins. The functional carboxy region (100-120 amino acids in each monomer) is released into the extracellular compartment to bind membrane receptors on target cells. There are a series of extracellular proteins that antagonize or otherwise alter the function of BMPs; these proteins include Glypican-3, Noggin, Chordin, Cerberus, and Follistatin (Fainsod et al., Mech. Dev. 63:39-50 (1997), Grisaru et al., Dev. Biol. 231:31-46 (2001), Holley et al., Cell 86:607-617 (1996), Iemura et al., Proc. Natl. Acad. U.S.A. 95:9337-9342 (1998), Jackson et al., Development 124:4113-4120 (1997), Paine-Saunders et al., Dev. Biol. 225:179-187 (2000), Piccolo et al., Cell 86:589-598 (1996), Re'em-Kalma et al., Proc. Natl. Acad. Sci. U.S.A. 92:12141-12145 (1995), Sasai et al., Nature 376:333-336 (1995), Zimmerman et al., Cell 86:599-606 (1996)). Type I and II BMP receptors are differentially expressed in various tissues, but both are indispensable for signal transduction. At the time of ligand binding, the type 1 and 2 BMP receptors form heterotetrameric-activated receptor complexes, which include two pairs of type 1 and 2 receptor complexes (Moustakas et al., Genes Dev. 16:67-87 (2002). Both receptor types are essential for signal transduction (Hogan, Genes Dev. 10:1580-1594 (1996), Nellen et al., Cell 78:225-237 (1994), Ruberte et al., Cell 80:889-897 (1995), Ten Dijke et al., Curr. Opin. Cell Biol. 8:139-145 (1996), Weis-Garcia et al., EMBO J. 15:276-289 (1996), Wrana et al., Nature 370:341-347 (1994)). Type 2 receptors have constitutively active kinase activity to phosphorylate type 1 receptors at the time of ligand binding. Phosphorylated type 1 receptors signal to downstream target proteins.
Type I BMP receptors signal through Smad proteins (Smad 1/5), which are important in relaying the BMP signal from the receptors to the target genes in the nucleus. When being released from the receptor, the phosphorylated Smad proteins associate with the related protein Smad4, which acts as a shared partner. This complex enters the nucleus, and participates in gene transcription with other transcription factors.
It has been little known that type 1 BMP receptor proteins, which play an important role in signaling, have improvement effects in wrinkles and atopic dermatitis.
Wrinkles are formed by the repeated movement of muscles in a particular direction for a long time, and are influenced by age, external environment, UV radiation, and the like. That is, human skin fibroblasts in the dermis layer are aged with the age of the skin tissue, so that the ability to generate fibers and substrates is reduced. Therefore, the amount of substrates is generally decreased, and thus the skin becomes thinned and inelastic, leading to the formation of wrinkles. Moreover, the exposure of the skin to UV radiation results in free radicals and reactive oxygen species (ROS), which are mainly causative of the damage of skin cells. These may generate age spots by inducing DNA damage and attacking the cell membrane structure, and accelerate wrinkle formation by attacking collagen and fibers which keep the skin to be moist, smooth, flexible, and elastic. Various methods for reducing skin wrinkles that are formed due to the external environment or internal mechanism have been supposed.
Meanwhile, atopy refers to an innate allergic reaction to food or other inhalable materials, but most of atopic diseases are intractable diseases of which causes are not clear Atopic dermatitis occurs in people who have an inherited predisposition to eczema, asthma, hay fever, allergy, and the like in many cases, but more causes thereof are known to be environmental factors such as residential pollution in modern cities. Atopic dermatitis is a chronic skin disease that tends to be chronic and recurrent starting from infant eczema called congenital fever.
Atopic dermatitis occurs in 10-20% of children and 1-3% of adults. According to the age, the symptoms thereof start from under one year old for 60% of infant patients and under five years old for 90% of infant patients. It is estimated that 4% of Korea's total population (about 185 million people) have atopic symptoms. The number of people with atopic symptoms is still increasing, which can be verified from recent research that four out of ten children under 6 years old living in Seoul suffered from atopic dermatitis (as reported by the Dong-A Ilbo on Dec. 27, 2005).
Symptoms of atopic dermatitis in infants are much improved by about 3-5 years old, but some cases continue until adolescence or adulthood. In recent years, the onset of atopic patients even after adolescence is increasing. For atopic dermatitis treatment, there are: a skin care method, in other words, softening the dry, cracked, and thickened skin to prevent the easy penetration of causative allergens, microorganisms, and other stimulating factors into the skin; a method of checking and removing accurate allergic causatives; a method of applying topical anti-inflammatory drugs and antibiotics; and the like.
Throughout the entire specification, many papers and patent documents are referenced and their citations are represented. The disclosures of cited papers and patent documents are entirely incorporated by reference into the present specification, and the level of the technical field within which the present invention falls and details of the present invention are explained more clearly.